Although the exact mechanism of interaction of ethanol (EtOH) with its neuronal targets is not yet understood, there is evidence that EtOH interacts with specific neuronal membrane receptor proteins to alter their normal function. Examples of receptors for which evidence supports a direct interaction with EtOH include; GABA-A, glutamate and several serotonin receptors. Newly developed methods for targeted alteration of gene function offer the possibility of establishing a cause and effect relationship between an action of EtOH on a molecular target and an EtOH-induced behavioral change. The current proposal focuses on the function of one such protein hitherto unexplored, namely cannabinoid (CB1) receptor in EtOH drinking and EtOH-related behaviors. Studies have indicated that there are genetic differences in the density and affinity of CB1 receptors in the brains of two strains of mouse found to differ in their preferences for EtOH. It has been demonstrated that administration of CB1 receptor antagonists reduced EtOH intake in EtOH-preferring mice. Based on these findings it is hypothesized that the genetically based differences in the brain levels and distribution of endocannabinoid ANA and CB1 receptors influence EtOH drinking behavior, and genetic manipulation through disruption of the gene for CB1 receptor protein will modulate the CB1-ergic system and the behavioral effects of EtOH. The Specific Aims are: (1) to generate CBI receptor knockout mice with two different genetic backgrounds (2) study the effect of gene disruption on (2) the levels and distribution of anandamide and its receptor (CB1) in various brain regions, EtOH drinking, and other EtOH-related behaviors, (4) the effects of CB1 receptor agonist and antagonist on EtOH drinking and other EtOH-related behaviors, and (5) to investigate the dopamine release in nucleus accumbens. The long-term goal is to develop medication for treatment of problems associated with alcohol abuse and alcoholism, which would be comparable to medical use of marijuana. Studies with synthetic analogues of ANA or other agonists and antagonists will open up new avenues in alcohol research.